New 2-(2-pyridyl)piperidines: synthesis, complexation of palladium and catalytic activity in Suzuki reaction

Article abstract of DOI:10.1016/j.tetlet.2007.12.125

The syntheses of novel 2-(2-pyridyl)-6-alkyl piperidines are reported using intramolecular Mannich-based methodology. Preliminary evaluation of the catalytic activity of the corresponding (diamine)Pd(II) complexes in the preparation of biaryl derivatives through Suzuki-type coupling reaction showed high to quantitative conversions and catalyst loadings as low as 10^-3 mol %.

Full text of DOI:10.1016/j.tetlet.2007.12.125

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1706–1709
New 2-(2-pyridyl)piperidines: synthesis, complexation of palladium
and catalytic activity in Suzuki reaction q
Bertrand Puget a, Jean-Philippe Roblin a, Damien Prim b,*, Yves Troin a,*
a Laboratoire de Chimie des He´te´rocycles et des Glucides, EA 987, Ecole Nationale Supe´rieure de Chimie de Clermont-Ferrand,
`
Universite´ Blaise Pascal, BP 187, 63174 Aubiere cedex, France
b Institut Lavoisier de Versailles, UMR CNRS 8180, Universite´ de Versailles-Saint-Quentin-en-Yvelines, 78035 Versailles cedex, France
Received 26 September 2007; revised 19 December 2007; accepted 21 December 2007
Available online 8 January 2008
Abstract
The syntheses of novel 2-(2-pyridyl)-6-alkyl piperidines are reported using intramolecular Mannich-based methodology. Preliminary
evaluation of the catalytic activity of the corresponding (diamine)Pd(II) complexes in the preparation of biaryl derivatives through
Suzuki-type coupling reaction showed high to quantitative conversions and catalyst loadings as low as 10ꢀ3 mol %.
Ó 2008 Elsevier Ltd. All rights reserved.
Vicinal diamines are common functional motifs in bio-
active compounds.1 Over the course of the past decades,
1,2-diamine derivatives also found applications as tools in
organic synthesis2 and in transition-metal-assisted cataly-
sis.3 Despite increasing reports in the latter area, there is
a steady demand for original, easily accessible diamine
Scheme 1.
ligands. As part of a programme directed towards the pre-
paration of new aza-heterocycles and their applications to
the design of new ligands,4 we envisioned the preparation
(2-pyridyl)-6-isopropyl-cis piperidine derivatives (Scheme
of 2-(2-aryl)-6-alkyl piperidines.
2) and their corresponding Pd(II) complexes together with
the evaluation of their potential catalytic activity through
the Suzuki coupling reaction.8
Indeed, in the last three decades, the Suzuki reaction has
become one of the most popular and general catalytic way
to create carbon–carbon bonds and thus found widespread
applications in organic synthesis. Many active catalytic
systems have been developed9 to improve the stability of
These compounds could be easily obtained through an
intramolecular Mannich type reaction between a protected
b-amino ketone and an aromatic aldehyde, which led pre-
dominantly to the 2,6-cis derivatives5 (Scheme 1). This
reaction is of wide scope as it can be applied to obtain var-
ious R and R0 substituents and this methodology has been
successfully applied to the synthesis of numerous alka-
loids.6,7 We wish to report herein the synthesis of new 2-
q
´
This work has been presented at JCO (Journees de Chimie Organique)
at Palaiseau in September 2007.
*
Corresponding authors. Tel.: +33 1 39 25 44 54; fax: +33 1 39 25 44 52
(D.P.); tel.: +33 4 73 40 71 39; fax: +33 4 73 40 70 08 (Y.T.).
E-mail addresses: prim@chimie.uvsq.fr (D. Prim), Yves.Troin@
univ-bpclermont.fr (Y. Troin).
Scheme 2.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.125

B. Puget et al. / Tetrahedron Letters 49 (2008) 1706–1709
1707
palladium-based catalyst and to increase their efficiency.
Besides bis-phosphine ligands, several nitrogen containing
ligands have proved to be useful for the preparation of
biaryl-type compounds.4,10a–f However, little attention has
been paid to the use of piperidyl compounds as potent tran-
sition metal ligands. To the best of our knowledge, pyridine-
piperidine bidentate ligands have not been yet described in
palladium based catalysis.
So, aminoketal 1 was easily prepared in three steps and
good overall yield (80%) by Michael addition of phthal-
imide to 5-methyl-3-hexen-2-one in the presence of Triton
BÒ as the catalyst, followed by acetalization with 1,3 pro-
pane diol and hydrazonolysis of the phthalimide moiety.
Condensation of 1 with commercially available 2-pyridine
carboxaldehyde 2, under our standard acidic cyclization
conditions,6a,b cleanly afforded the expected 2,6-cis-disub-
stituted piperidine 3 in high yield (80%) and high diastereo-
selectivity (up to 95%) (Scheme 2). Relative configuration
of piperidine 3 was unambiguously established from the
1H NMR data, notably with the signals relative to axial
H-3 and axial H-5 showing typical coupling constants for
a 2,6-diequatorial disubstitution in a chair conformation.5
We next envisioned the modification and/or rigidifica-
tion of the piperidine backbone, which may strongly influ-
ence the catalytic process, and turned our attention to keto
and dihydro derivatives 5 and 7. Cleavage of the dioxane
appendage of compound 3 was then achieved in two steps
since we have demonstrated that deacetalization was best
realized if the nitrogen of the piperidine ring was protected.
Thus, the treatment of piperidine 3 with benzyl chlorofor-
mate in biphasic medium11 led to carbamate 4 in very good
yield. Then, the reaction of 4 with trifluoroacetic acid
followed by catalytic hydrogenation furnished piperidone
5. On the other hand, treatment of 4 with an excess of
ethanedithiol in dichloromethane in the presence of BF3.
Et2O afforded quantitatively the dithiolane derivative 6.
Subsequent hydrogenolysis of 6 was completely and cleanly
achieved in the presence of freshly prepared W2 Raney-
nickel in refluxing methanol and furnished piperidine 712
in good overall yield (Scheme 3).
Compounds 3, 5 and 7 were now treated with Na2PdCl4
under classical conditions13 to give the expected Pd (II)
complexes 8–10 in high yields (Scheme 4). The reaction
proceeds smoothly at room temperature in freshly distilled
methanol. After 24 h, the precipitated complexes are col-
lected by filtration. These palladium complexes are stable
on air and they could be either purified by silica gel chro-
matography if necessary. NMR data of complexes 8–10
were in good agreement with their respective structure.
Indeed, characteristic positive shieldings ranging from
0.08 to 0.43 ppm for pyridine protons were observed
between ligands 3, 5, 7 and their complexes 8–10, thus con-
firming coordination by the metal centre.
Scheme 3. Reagents and conditions: (i) CBzCl, CH2Cl2, Na2CO3; (ii) TFA
aq 40%; (iii) H2, Pd/C; (iv) HS(CH2)2SH, BF3(OEt)2, CH2Cl2; (v) H2,
Raney-Ni, EtOH.
Scheme 4.
shown in Table 1. Classical reaction conditions (K2CO3 as
the base and a mixture of DMF/H2O (95:5) as the solvent)
were first used. Gratifyingly, the model compound could be
quantitatively obtained using 1% of catalyst 8 (Table 1,
entry 1). Subsequent reaction analysis was performed by
1H NMR spectroscopy of crude reaction mixtures to give
an accurate assessment of product distribution based on
the chemical shift of the aldehyde proton of both the prod-
uct and the substrate. Interestingly, decrease of the catalyst
loading to 0.1 and further to 0.01 mol % led to quantitative
conversion within 1 h 30 min (entries 2 and 3, respectively).
In addition, reaction times could be optimized to 30 min by
changing the base, moving from K2CO3 to Cs2CO3 or
K3PO4ꢁ7H2O (entries 4 and 5) without the loss of catalytic
activity. Although if complete conversion could be observed
in the latter case, a small amount of benzaldehyde, arising
from hydrodehalogenation of the starting halide, was con-
comitantly obtained (less than 5%, entry 5). It is also worth
noting that optimal reaction temperature was 110 °C.
Effectively, decreasing of the reaction temperature resulted
in prolonged heating time for the same quantitative yield.
Having in hands a set of three new complexes, we started
to evaluate their catalytic activity in Suzuki-type reactions.
Preliminary results based on the preparation of 4-biphenyl-
carbaldehyde 11, as model compound (Scheme 5), are
Scheme 5.

1708
B. Puget et al. / Tetrahedron Letters 49 (2008) 1706–1709
Table 1
Table 2
Optimization of reaction conditionsa at 110 °C
Suzuki reaction15 of aryl halide with boronic acid using complex 10 as the
catalysta
E
mol % Cat.
Complex Base
Time
Yieldb (%)
(conversion)
E
1
Ar–Br
Boronic acid
Mol %
Time
Yieldb (%)
90
1
2
3
4
5
6
7
8
1
0.1
8
8
K2CO3
1 h 30 min 96
1 h 30 min (>98)
1 h 30 min (>98)
6 ꢂ 10ꢀ3
30 min
K2CO3
K2CO3
Cs2CO3
0.01
0.01
0.01
0.01
0.01
0.006
8
8
30 min
(>98)
(>98)c
80
(>98)
90
8
K3PO4ꢁ7H2O 30 min
2
3
10ꢀ2
1 h
2 h
99
99
9
K3PO4ꢁ7H2O 2 h
10
10
K3PO4ꢁ7H2O 30 min
K3PO4ꢁ7H2O 30 min
a
Reaction conditions: 4-bromobenzaldehyde (0.5 mmol), phenylbo-
6 ꢂ 10ꢀ2
ronic acid (0.55 mmol), base (1.25 mmol) 1 ml DMF/H2O (95:5).
b
Isolated yields.
c
Obtained as
benzaldehyde.
a 95:5 mixture of expected biphenyl product and
We next evaluated the catalytic activity of complexes 9
and 10. Complex 9 bearing the keto moiety revealed less
effective than the ketal analogue 8 (entry 6). The more rigid
conformation of the piperidone cycle may account for the
observed lesser activity. Finally, complex 1014 used as the
catalyst proved efficient in the Suzuki-type reaction.
Indeed, catalyst loading as low as 1 ꢂ 10ꢀ2 and 6 ꢂ 10ꢀ3
allowed the preparation of 11 in quantitative and 90%
yield, respectively, within 30 min (entries 7 and 8). In addi-
tion, no reduction of the starting halide leading to benzal-
dehyde could be observed under these conditions. Catalytic
system based on complex 10 thus seems to be the catalyst
of choice in these reactions from practical considerations.
Then, catalyst 10 was used in a variety of Suzuki-type
coupling reactions and the results obtained were collected
as shown in Table 2. We first examined the influence of
the substitution of both the aromatic halide and boronic
acid, by electron withdrawing or electron donating groups
on the formation of the coupling product. The latter are
well tolerated in this reaction leading to quantitative yields
of the corresponding biaryls (entries 2, 3 and 5). Even the
presence of a strong withdrawing NO2 substituent on the
aromatic boronic acid afforded the expected biphenyl com-
pound in 85% yield after 5 h (entry 5). As illustrated in
compounds 13, 15, 16, under our conditions, the coupling
reactions seem not to be sensitive to ortho-substitution pat-
tern of both the aromatic halide and boronic acid. In addi-
tion, naphthalene bromides have been successfully coupled
with (4-methoxyphenyl)boronic acid and (2-methyl-
naphthyl)boronic acid, using 6 ꢂ 10ꢀ3 mol % catalyst
loading, affording compounds 14 and 16 in high yields
(entries 4 and 6).
4
6 ꢂ 10ꢀ3
1 h
95
2 h
5 h
66
85
6 ꢂ 10ꢀ2
5
6
6 ꢂ 10ꢀ3
2 h
95
7
8
6 ꢂ 10ꢀ2
6 ꢂ 10ꢀ2
2 h
2 h
99
99
9
6 ꢂ 10ꢀ2
12 h
50
a
Reaction conditions: aryl halide (0.5 mmol) boronic acid (0.55 mmol),
K3PO4ꢁ7H2O (1.25 mmol), DMF/H2O (95:5) 1 ml, 110 °C.
b
Isolated yields.
tion of the catalytic activity of these complexes addresses
the potentiality of this new ligand series in the preparation
of biaryls through Suzuki-type coupling reactions. Further
development of both the asymmetric synthesis of such
ligands and the asymmetric Suzuki reaction is now under
investigation.
Finally, the coupling reaction of phenylboronic acid with
both p-excessive and p-deficient heterocycles was carried
out leading to 17 and 18, respectively, in nearly quantitative
yields (entries 7 and 8).
In summary, new 2-(2-pyridyl)-6-isopropyl cis piperi-
dines have been successfully synthesized using intramolecu-
lar Mannich methodology. These new bidendate strained
ligands with two different chelation sites permit the prepara-
tion of new palladium(II) complexes. Preliminary evalua-
Acknowledgements
We are grateful to MENRT-France for a Grant (B.
Puget) and the CNRS, the Universite de Versailles-Saint-
Quentin-en-Yvelines and ENSCCF for financial support.
´

B. Puget et al. / Tetrahedron Letters 49 (2008) 1706–1709
1709
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12. Spectral data 1H NMR: dH (300 MHz, CDCl3) 8.52 (d, J = 3.0 Hz,
1H), 7.76 (td, J = 7.7 Hz, J = 0.8 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H),
7.27 (td, J = 7.4 Hz, J = 1.2 Hz, 1H), 4.38 (dd, J = 12.0 Hz,
J = 2.8 Hz, 1H), 3.22 (m, 1H), 2.44 (m, 1H), 1.83–2.09 (m, 5H),
1.61 (m, 2H); 1.07 (d, J = 6.8 Hz, 3H); 1.01 (d, J = 6.8 Hz, 3H). 13C
NMR: dC (75 MHz, CDCl3) 155.6, 149.2, 137.9, 124 122.6, 62.2, 60.3,
30.3, 30.1, 23.3, 22.5, 19.4, 16.7.
References and notes
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15. Typical experimental procedure for the Suzuki reaction:
A mixture of p-bromobenzaldehyde (0.50 mmol, 92 mg), phenyl
boronic acid (0.55 mmol, 67 mg), Pd-complex 10 (6 ꢂ 10ꢀ3 mol %,
330 ll of a 1/100 diluted 9 mM solution in 95:5 DMF/H2O) and
K3PO4ꢁ7H2O (1.25 mmol, 423 mg) in 1 ml DMF/H2O (95:5) freshly
prepared with degassed and distilled solvents was stirred at 110 °C for
30 min. After the mixture was washed with water, extracted with
ether, dried over magnesium sulfate and concentrated under vacuum,
the residue was purified by flash column chromatography (petroleum
ether) to afford biphenyl-4-carbaldehyde 11 (82 mg, 90%).
7. For successful application of our methodology in enantioselective
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Lett. 2003, 5, 5011–5014.
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´
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